This invention relates to compounds and pharmaceutical compositions, and to methods of using same in the treatment of psychiatric disorders and neurological diseases including major depression, anxiety-related disorders, post-traumatic stress disorder, supranuclear palsy and feeding disorders.
Corticotropin releasing factor (herein referred to as CRF), a 41 amino acid peptide, is the primary physiological regulator of proopiomelanocortin (POMC)-derived peptide secret.gland [J. Rivier et al., Proc. Nat. Acad. Sci. (USA) 80:4851 (1983); W. Vale et al., Science 213:1394 (1981)]. In addition to its endocrine role at the pituitary gland, immunohistochemical localization of CRF has demonstrated that the hormone has a broad extrahypothalamic distribution in the central nervous system and produces a wide spectrum of autonomic, electrophysiological and behavioral effects consistent with a neurotransmitter or neuromodulator role in brain. [W. Vale et al., Rec. Prog. Horm. Res. 39:245 (1983); G. F. Koob, Persp. Behav. Med. 2:39 (1985); E. B. De Souza et al., J. Neurosci. 5:3189 (1985)]. There is also evidence that CRF plays a significant role in integrating the response of the immune system to physiological, psychological, and immunological stressors [J. E. Blalock, Physiological Reviews 69:1 (1989); J. E. Morley, Life Sci. 41:527 (1987)].
Clinical data provide evidence that CRF has a role in psychiatric disorders and neurological diseases including depression, anxiety-related disorders and feeding disorders. A role for CRF has also been postulated in the etiology and pathophysiology of Alzheimer""s disease, Parkinson""s disease, Huntington""s disease, progressive supranuclear palsy and amyotrophic lateral sclerosis as they relate to the dysfunction of CRF neurons in the central nervous system [for review see E. B. De Souza, Hosp. Practice 23:59 (1988)].
In affective disorder, or major depression, the concentration of CRF is significantly increased in the cerebral spinal fluid (CSF) of drug-free individuals [C. B. Nemeroff et al., Science 226:1342 (1984); C. M. Banki et al., Am. J. Psychiatry 144:873 (1987); R. D. France et al., Biol. Psychiatry 28:86 (1988); M. Arato et al., Biol Psychiatry 25:355 (1989)]. Furthermore, the density of CRF receptors is significantly decreased in the frontal cortex of suicide victims, consistent with a hypersecretion of CRF [C. B. Nemeroff et al., Arch. Gen. Psychiatry 45:577 (1988)]. In addition, there is a blunted adrenocorticotropin (ACTH) response to CRF (i.v. administered) observed in depressed patients [P. W. Gold et al., Am J. Psychiatry 141:619 (1984); F. Holsboer et al., Psychoneuroendocrinology 9:147 (1984); P. W. Gold et al., New Eng. J. Med. 314:1129 (1986)]. Preclinical studies in rats and non-human primates provide additional support for the hypothesis that hypersecretion of CRF may be involved in the symptoms seen in human depression [R. M. Sapolsky, Arch. Gen. Psychiatry 46:1047 (1989)]. There is preliminary evidence that tricyclic antidepressants can alter CRF levels and thus modulate the numbers of CRF receptors in brain [Grigoriadis et al., Neuropsychopharmacology 2:53 (1989)].
There has also been a role postulated for CRF in the etiology of anxiety-related disorders. CRF produces anxiogenic effects in animals and interactions between benzodiazepine/non-benzodiazepine anxiolytics and CRF have been demonstrated in a variety of behavioral anxiety models [D. R. Britton et al., Life Sci. 31:363 (1982); C. W. Berridge and A. J. Dunn Regul. Peptides 16:83 (1986)]. Preliminary studies using the putative CRF receptor antagonist a-helical ovine CRF (9-41) in a variety of behavioral paradigms demonstrate that the antagonist produces xe2x80x9canxiolytic-likexe2x80x9d effects that are qualitatively similar to the benzodiazepines [C. W. Berridge and A. J. Dunn Horm. Behav. 21:393 (1987), Brain Research Reviews 15:71 (1990)]. Neurochemical, endocrine and receptor binding studies have all demonstrated interactions between CRF and benzodiazepine anxiolytics providing further evidence for the involvement of CRF in these disorders. Chlordiazepoxide attenuates the xe2x80x9canxiogenicxe2x80x9d effects of CRF in both the conflict test [K. T. Britton et al., Psychopharmacology 86:170 (1985); K. T. Britton et al., Psychopharmacology 94:306 (1988)] and in the acoustic startle test [N. R. Swerdlow et al., Psychopharmacology 88:147 (1986)] in rats. The benzodiazepine receptor antagonist (Ro15-1788), which was without behavioral activity alone in the operant conflict test, reversed the effects of CRF in a dose-dependent manner while the benzodiazepine inverse agonist (FG7142) enhanced the actions of CRF [K. T. Britton et al., Psychopharmacology 94:306 (1988)].
The mechanisms and sites of action through which the standard anxiolytics and antidepressants produce their therapeutic effects remain to be elucidated. It has been hypothesized however, that they are involved in the suppression of the CRF hypersecretion that is observed in these disorders. Of particular interest is that preliminary studies examining the effects of a CRF receptor antagonist (a-helical CRF9-41) in a variety of behavioral paradigms have demonstrated that the CRF antagonist produces xe2x80x9canxiolytic-likexe2x80x9d effects qualitatively similar to the benzodiazepines [for review see G. F. Koob and K. T. Britton, In: Corticotropin-Releasing Factor: Basic and Clinical Studies of a Neuropeptide, E. B. De Souza and C. B. Nemeroff eds., CRC Press p221 (1990)].
Several published patent applications disclose corticotropin releasing factor antagonist compounds. Among these are DuPont Merck PCT application U.S. Pat. No. 94/11050, Pfizer WO 95/33750, Pfizer WO 95/34563, and Pfizer WO 95/33727. U.S. Pat. No. 5,424,311 discloses antiviral use of azaquinoxalines of the formula: 
in which V, W, Y and Z are CH, CR1, or N; X can be oxygen, sulfur or NR2; R1 can be alkyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, or alkylamino; R2, R3, R4 and R5 can be hydrogen, alkyl, aryl or heteroaryl.
U.S. Pat. No. 5,283,244 discloses glutamate receptor antagonizing activity of fused pyrazine derivatives of the the formula: 
wherein Z represents C or N; R1 represents a diazole or triazole substituent; and the other R groups represent hydrogen or various substituents such as alkyl, phenyl, or heterocycle.
This invention is a method of treating an affective disorder, anxiety, depression, irritable bowel syndrome, post-traumatic stress disorder, supranuclear palsy, immune suppression, Alzheimer""s disease, gastrointestinal disease, anorexia nervosa or other feeding disorder, drug or alcohol withdrawal symptoms, drug addiction, or inflammatory disorder in a mammal comprising administering to the mammal a therapeutically effective amount of a CRF antagonist compound of formula I: 
or a pharmaceutically accetable salt or prodrug thereof, wherein:
A is N or Cxe2x80x94R11;
X is H, OR1, S(O)nR1, NR1R2, CR1R2R3, phenyl (optionally substituted with 1-4 groups independently chosen from halogen, C1-C4 haloalkyl, nitro, C1-C4 alkyl, C2-C5 carboalkoxy, cyano, OH, C1-C4 alkoxy, SH, C1-C4 alkylthio, NH2, C1-C4 alkylamino, C2-C8 dialkylamino, or phenyl) or heteroaryl (optionally substituted at one to all valence-allowed positions with groups independently chosen from halogen, C1-C4 haloalkyl, nitro, C1-C4 alkyl, C2-C5 carboalkoxy, cyano, OH, C1-C4 alkoxy, SH, C1-C4 alkylthio, NH2, C1-C4 alkylamino, C2-C8 dialkylamino, or phenyl);
n is 0, 1 or 2;
R1 is C1-C12 alkyl, C2-C12 alkoxyalkyl, C3-C12 cycloalkyl, C4-C12 cycloalkylalkyl, C2-C12 alkenyl, C2-C12 alkynyl, aryl-(C1-C12 alkyl), C3-C12 dialkylaminoalkyl, C2-C13 cyanoalkyl, C2-C5 carboalkoxy-(C1-C12 alkyl), phenyl (optionally substituted with 1-4 groups independently chosen from halogen, C1-C4 haloalkyl, nitro, C1-C4 alkyl, C2-C5 carboalkoxy, cyano, OH, C1-C4 alkoxy, SH, C1-C4 alkylthio, NH2, C1-C4 alkylamino, C2-C8 dialkylamino, or phenyl), or heteroaryl (optionally substituted at one to all valence-allowed positions with groups independently chosen from halogen, C1-C4 haloalkyl, nitro, C1-C4 alkyl, C2-C5 carboalkoxy, cyano, OH, C1-C4 alkoxy, SH, C1-C4 alkylthio, NH2, C1-C4 alkylamino, C2-C8 dialkylamino, or phenyl);
R2 and R3 are independently chosen from H, C1-C12 alkyl, C2-C12 alkoxyalkyl, C3-C12 cycloalkyl, C4-C12 cycloalkylalkyl, C2-C12 alkenyl, C2-C12 alkynyl, aryl-(C1-C12 alkyl), C3-C12 dialkylaminoalkyl, C2-C13 cyanoalkyl, C1-C4 carboalkoxy, C2-C12 carboalkoxyalkyl, C(xe2x95x90O)CH3, phenyl (optionally substituted with 1-4 groups independently chosen from halogen, C1-C4 haloalkyl, nitro, C1-C4 alkyl, C2-C5 carboalkoxy, cyano, OH, C1-C4 alkoxy, SH, C1-C4 alkylthio, NH2, C1-C4 alkylamino, C2-C8 dialkylamino, or phenyl), or heteroaryl (optionally substituted at one to all valence-allowed positions with groups independently chosen from halogen, C1-C4 haloalkyl, nitro, C1-C4 alkyl, C2-C5 carboalkoxy, cyano, OH, C1-C4 alkoxy, SH, C1-C4 alkylthio, NH2, C1-C4 alkylamino, C2-C8 dialkylamino, or phenyl);
R4 is H, C1-C12 alkyl, allyl, propargyl or benzyl (optionally substituted with 1-4 groups independently chosen from halogen, C1-C4 haloalkyl, nitro, C1-C4 alkyl, C2-C5 carboalkoxy, cyano, OH, C1-C4 alkoxy, SH, C1-C4 alkylthio, NH2, C1-C4 alkylamino, C2-C8 dialkylamino, or phenyl);
R1 and R4 may also optionally be taken together, along with the other four interconnected atoms, to form a ring of 5-9 total atoms, the structural sequence between the X group and the ring nitrogen atom consisting of the group (CH2)pW(CH2)q;
p and q are independently 0, 1 or 2;
W is CH2, C(CH3)2, C(xe2x95x90O), O, S or NCH3;
R5, R6, R7 and R8 are independently chosen from H, C1-C4 alkyl, allyl, propargyl, phenyl (optionally substituted with 1-4 groups independently chosen from halogen, C1-C4 haloalkyl, nitro, C1-C4 alkyl, C2-C5 carboalkoxy, cyano, OH, C1-C4 alkoxy, SH, C1-C4 alkylthio, NH2, C1-C4 alkylamino, C2-C8 dialkylamino, or phenyl) or benzyl (optionally substituted with 1-4 groups independently chosen from halogen, C1-C4 haloalkyl, nitro, C1-C4 alkyl, C2-C5 carboalkoxy, cyano, OH, C1-C4 alkoxy, SH, C1-C4 alkylthio, NH2, C1-C4 alkylamino, C2-C8 dialkylamino, or phenyl); R4, R5 and R6 may also be taken together, along with the two interconnecting atoms, to constitute either an imidazole or tetrazole ring, the imidazole ring being optionally substituted with 1-2 groups chosen independently from C1-C4 alkyl or phenyl;
R5 and R6 may also be taken together to be O, S or NR12;
R9 is phenyl (optionally substituted with 1-4 groups chosen from halogen, C1-C4 haloalkyl, C1-C4 alkyl, C2-C6 alkenyl, C1-C4 alkoxy, C1-C4 alkylthio, C1-C4 alkylsulfonyl, C2-C6 dialkylamino, nitro, C2-C5 carboalkoxy or cyano), pyridyl (optionally substituted with 1-4 groups chosen from halogen, C1-C4 haloalkyl, C1-C4 alkyl, C2-C6 alkenyl, C1-C4 alkoxy, C1-C4 alkylthio, C1-C4 alkylsulfonyl, C2-C6 dialkylamino, nitro, C2-C5 carboalkoxy or cyano), or pyrimidyl (optionally substituted with 1-4 groups chosen from halogen, C1-C4 haloalkyl, C1-C4 alkyl, C2-C6 alkenyl, C1-C4 alkoxy, C1-C4 alkylthio, C1-C4 alkylsulfonyl, C2-C6 dialkylamino, nitro, C2-C5 carboalkoxy or cyano)
R10 is H, C1-C4 alkyl or cyano;
R11 is H, C1-C4 alkyl or halogen;
R12 is H, C1-C4 alkyl or phenyl;
aryl is phenyl, biphenyl or naphthyl; and
heteroaryl is pyridyl, pyrimidinyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzthiazolyl, isoxazolyl or pyrazolyl.
Compounds of formula I, other than those in which R5 and R6 are taken together and are O, S or NR12, are novel. This invention includes the novel compounds of formula I and pharmaceutical compositions containing them.
Preferred compounds for use in the method of this invention are compounds of formula (I) wherein:
X is OR1, NR1R2, CR1R2R3, or phenyl (optionally substituted at the 2-position with CF3, nitro, halogen or cyano);
R1 is C1-C12 alkyl, C2-C12 alkoxyalkyl, C3-C12 cycloalkyl, C4-C12 cycloalkylalkyl, aryl-(C1-C12 alkyl), C3-C12 dialkylaminoalkyl, or phenyl (optionally substituted with 1-4 groups independently chosen from halogen, haloalkyl, nitro, C1-C4 alkyl, C2-C5 carboalkoxy, cyano, OH, C1-C4 alkoxy, SH, C1-C4 alkylthio, NH2, C1-C4 alkylamino, C2-C8 dialkylamino, or phenyl);
R4 is H or C1-C4 alkyl;
R5 and R6 are either H or C1-C4 alkyl;
R4, R5 and R6 may also be taken together, along with the two interconnecting atoms, to constitute a tetrazole ring;
R9 is phenyl (optionally substituted with 1-4 groups chosen from halogen, C1-C4 haloalkyl, C1-C4 alkyl, C2-C6 alkenyl, C1-C4 alkoxy, C1-C4 alkylthio, C1-C4 alkylsulfonyl, C2-C6 dialkylamino, nitro, C2-C5 carboalkoxy or cyano), 3-pyridyl (optionally substituted with 1-4 groups chosen from halogen, C1-C4 haloalkyl, C1-C4 alkyl, C2-C6 alkenyl, C1-C4 alkoxy, C1-C4 alkylthio, C1-C4 alkylsulfonyl, C2-C6 dialkylamino, nitro, C2-C5 carboalkoxy or cyano), or 5-pyrimidyl (optionally substituted with 1-4 groups chosen from halogen, C1-C4 haloalkyl, C1-C4 alkyl, C2-C6 alkenyl, C1-C4 alkoxy, C1-C4 alkylthio, C1-C4 alkylsulfonyl, C2-C6 dialkylamino, nitro, C2-C5 carboalkoxy or cyano);
R10 is CH3;
and R11 is H.
More preferred compounds in this invention are of the formula (I) wherein:
A is N;
X is NR1R2 or CR1R2R3;
R1 is C1-C6 alkyl or C2-C8 alkoxyalkyl;
R2 and R3 are independently H, C1-C6 alkyl or C2-C8 alkoxyalkyl;
R4 is H;
R5 and R6 are H;
R7 and R8 are independently H or CH3;
and R9 is phenyl (optionally substituted with 1-4 groups chosen from halogen, C1-C4 haloalkyl, C1-C4 alkyl, C2-C6 alkenyl, C1-C4 alkoxy, C1-C4 alkylthio, C1-C4 alkylsulfonyl, C2-C6 dialkylamino, nitro, C2-C5 carboalkoxy or cyano).
Specifically preferred because of their biological activity are the following compounds:
8-(2-bromo-4-isopropylphenyl)-4-(ethylbutylamino)-2-methyl-5,6,7,8-tetrahydropteridine;
8-(2-chloro-4,6-dimethoxyphenyl)-4-(ethylbutylamino)-2-methyl-5,6,7,8-tetrahydropteridine;
4-(ethylbutylamino)-2-methyl-8-(2,4,6-trimethyl-phenyl)-5,6,7,8-tetrahydropteridine;
and 4-(1-methoxy-2-butyl)amino-2-methyl-8-(2,4,6-trimethylphenyl)-5,6,7,8-tetrahydropteridine.
Many compounds of this invention have one or more asymmetric centers or planes. Unless otherwise indicated, all chiral (enantiomeric and diastereomeric) and racemic forms are included in the present invention. Many geometric isomers of olefins, Cxe2x95x90N double bonds, and the like can also be present in the compounds, and all such stable isomers are contemplated in the present invention. The compounds may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials. All chiral, (enantiomeric and diastereomeric) and racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomer form is specifically indicated.
The term xe2x80x9calkylxe2x80x9d includes both branched and straight-chain alkyl having the specified number of carbon atoms. xe2x80x9cAlkenylxe2x80x9d includes hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain, such as ethenyl, propenyl, and the like. xe2x80x9cAlkynylxe2x80x9d includes hydrocarbon chains of either a straight or branched configuration and one or more triple carbon-carbon bonds which may occur in any stable point along the chain, such as ethynyl, propynyl and the like. xe2x80x9cHaloalkylxe2x80x9d is intended to include both branched and straight-chain alkyl having the specified number of carbon atoms, substituted with 1 or more halogen; xe2x80x9calkoxyxe2x80x9d represents an alkyl group of indicated number of carbon atoms attached through an oxygen bridge; xe2x80x9ccycloalkylxe2x80x9d is intended to include saturated ring groups, including mono-, bi- or poly-cyclic ring systems, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and so forth. xe2x80x9cHaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d includes fluoro, chloro, bromo, and iodo.
The term xe2x80x9csubstitutedxe2x80x9d, as used herein, means that one or more hydrogen on the designated atom is replaced with a selection from the indicated group, provided that the designated atom""s normal valency is not exceeded, and that the substitution results in a stable compound. When a substitent is keto (i.e., xe2x95x90O), then 2 hydrogens on the atom are replaced.
Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. By xe2x80x9cstable compoundxe2x80x9d or xe2x80x9cstable structurexe2x80x9d is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
The term xe2x80x9cappropriate amino acid protecting groupxe2x80x9d means any group known in the art of organic synthesis for the protection of amine or carboxylic acid groups. Such amine protecting groups include those listed in Greene and Wuts, xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d John Wiley and Sons, New York (1991) and xe2x80x9cThe Peptides: Analysis, Synthesis, Biology, Vol. 3, Academic Press, New York (1981), the disclosure of which is hereby incorporated by reference. Any amine protecting group known in the art can be used. Examples of amine protecting groups include, but are not limited to, the following: 1) acyl types such as formyl, trifluoroacetyl, phthalyl, and p-toluenesulfonyl; 2) aromatic carbamate types such as benzyloxycarbonyl (Cbz) and substituted benzyloxycarbonyls, 1-(p-biphenyl)-1-methylethoxycarbonyl, and 9-fluorenylmethyloxycarbonyl (Fmoc); 3) aliphatic carbamate types such as tert-butyloxycarbonyl (Boc), ethoxycarbonyl, diisopropylmethoxycarbonyl, and allyloxycarbonyl; 4) cyclic alkyl carbamate types such as cyclopentyloxycarbonyl and adamantyloxycarbonyl; 5) alkyl types such as triphenylmethyl and benzyl; 6) trialkylsilane such as trimethylsilane; and 7) thiol containing types such as phenylthiocarbonyl and dithiasuccinoyl.
The term xe2x80x9camino acidxe2x80x9d as used herein means an organic compound containing both a basic amino group and an acidic carboxyl group. Included within this term are natural amino acids, modified and unusual amino acids, as well as amino acids which are known to occur biologically in free or combined form but usually do not occur in proteins. Included within this term are modified and unusual amino acids, such as those disclosed in, for example, Roberts and Vellaccio (1983) The Peptides, 5: 342-429, the teaching of which is hereby incorporated by reference. Modified or unusual amino acids which can be used to practice the invention include, but are not limited to, D-amino acids, hydroxylysine, 4-hydroxyproline, an N-Cbz-protected amino acid, ornithine, 2,4-diaminobutyric acid, homoarginine, norleucine, N-methylaminobutyric acid, naphthylalanine, phenylglycine, xcex2-phenylproline, tert-leucine, 4-aminocyclohexylalanine, N-methyl-norleucine, 3,4-dehydroproline, N,N-dimethylaminoglycine, N-methylaminoglycine, 4-aminopiperidine-4-carboxylic acid, 6-aminocaproic acid, trans-4-(aminomethyl)-cyclohexanecarboxylic acid, 2-, 3-, and 4-(aminomethyl)-benzoic acid, 1-aminocyclopentanecarboxylic acid, 1-aminocyclopropanecarboxylic acid, and 2-benzyl-5-aminopentanoic acid.
The term xe2x80x9camino acid residuexe2x80x9d as used herein means that portion of an amino acid (as defined herein) that is present in a peptide.
The term xe2x80x9cpeptidexe2x80x9d as used herein means a compound that consists of two or more amino acids (as defined herein) that are linked by means of a peptide bond. The term xe2x80x9cpeptidexe2x80x9d also includes compounds containing both peptide and non-peptide components, such as pseudopeptide or peptide mimetic residues or other non-amino acid components. Such a compound containing both peptide and non-peptide components may also be referred to as a xe2x80x9cpeptide analogxe2x80x9d.
The term xe2x80x9cpeptide bondxe2x80x9d means a covalent amide linkage formed by loss of a molecule of water between the carboxyl group of one amino acid and the amino group of a second amino acid.
The term xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d includes acid or base salts of the compounds of formulas (I) and (II). Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
Pharmaceutically acceptable salts of the compounds of the invention can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington""s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure of which is hereby incorporated by reference. xe2x80x9cProdrugsxe2x80x9d are considered to be any covalently bonded carriers which release the active parent drug of formula (I) or (II) in vivo when such prodrug is administered to a mammalian subject. Prodrugs of the compounds of formula (I) and (II) are prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compounds. Prodrugs include compounds wherein hydroxy, amine, or sulfhydryl groups are bonded to any group that, when administered to a mammalian subject, cleaves to form a free hydroxyl, amino, or sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of formulas (I) and (II); and the like.
The term xe2x80x9ctherapeutically effective amountxe2x80x9d of a compound of this invention means an amount effective to antagonize abnormal level of CRF or treat the symptoms of affective disorder, anxiety or depression in a host.
Synthesis
Synthesis of compounds of Formula (I) wherein A=N may begin with amidine compounds of Formula (II) (Scheme I), which are available commercially or synthetically from heating a nitrile compound and an ammonium salt. Compound (II) may then be condensed with a malonate ester (using conditions such as sodium in ethanol) to give a dihydroxy-pyrimidine compound of Formula (III). Nitration at the 5-position may be accomplished through the use of such conditions as concentrated nitric acid with or without the presence of another acid such as concentrated sulfuric or glacial acetic. The hydroxy groups of the nitrated compound of Formula (IV) may then be converted into leaving groups (Y), which include chloro, bromo, toluenesulfonate, or methanesulfonate. The dichloro compound (Formula (V), Yxe2x95x90Cl) may be prepared from the dihydroxy by a reagent such as phosphorus oxychloride, with or without the assistance of a catalyst such as diethylaniline. The bis(toluenesulfonate) compound (Formula (V), Yxe2x95x90OSO2C6H4CH3), may be prepared from the dihydroxy compound by treatment with a reagent such as toluenesulfonic anhydride. Careful addition one equivalent of a suitable form of a compound Xxe2x80x94H to the compound of Formula (V) results in replacement of one of the Y groups with X. This is of particular utility when the X group represents a nucleophilic atom, such as nitrogen, sulfur or oxygen. Conditions which will facilitate this transformation include the optional presence of bases such as sodium hydride, triethylamine, diisopropylethylamine or 
potassium carbonate, in solvents such as tetrahydrofuran, dimethylformamide, dimethylsulfoxide, methylene chloride, acetonitrile or ethanol, at appropriate temperatures.
Alternatively, in the case where X represents a group without a corresponding nucleophilic compound Xxe2x80x94H being available, one may condense a compound of Formula (II) with an appropriately-substituted ketoester (using conditions similar to those for the malonate condensation) to obtain a compound of Formula (VII). Nitration conditions similar to those described above may then be used to prepare the nitro compound (VIII). Conversion of the pyrimidone group to the desired Y group may then be accomplished using the same conditions as described above for the transformation of (IV) to (V).
A third alternative involves treatment of the compound of Formula (V) with a compound R9xe2x80x94NH2. Conditions may be found for each Y group so that one Y group is replaced by R9xe2x80x94NH, and the other is hydrolyzed to the pyrimidone (compound Formula (IX)). For example, for Yxe2x95x90Cl, this conversion may be effected by slow addition of a dimethylsulfoxide solution of one equivalent of R9xe2x80x94NH2 to a dimethylsulfoxide solution of compound (V), followed by aqueous workup. The pyrimidione of Formula (IX) may be converted to Y-bearing compound (Formula (X)) using the conditions described above for (IV) to (V). The Y group can then be replaced with X analogously to the transformation of (V) to (VI) to give a compound of Formula (XI).
Alternatively, the compound of Formula (VI) may be converted to the compound of Formula (XI) by treatment with the compound R9xe2x80x94NH2. Suitable conditions for this reaction include treatment with excess sodium hydride in refluxing toluene or heating the two compounds together in an alcoholic solvent (ethanol, propanol, butanol, ethylene glycol, ethoxyethoxyethanol) or other polar, aprotic solvents (such as dimethylformamide, 1,4-dioxane, dimethoxyethane or diglyme) without a base to effect the coupling.
Scheme II shows the appending of the second ring onto the pyrimidine ring. The nitro group in the compound of Formula (XI) can be reduced to an amino group using conditions such as sodium dithionite, catalytic hydrogenation, iron or zinc. The compound of Formula (XII) may be treated with a base such as sodium hydride (in solvents such as dimethylformamide, dimethyl sulfoxide, 1,4-dioxane, tetrahydrofuran, etc.), followed by a reagent of the general formula Yxe2x80x94CR7R8xe2x80x94CO2R, where Y is halogen or psuedohalogen, and the structure of R is only important if 
removal of the group prior to cyclization is desired. Cyclization of the compound of Formula (XIV) may be accomplished by heating in a solvent such as ethanol, dimethylformamide, etc. at temperatures ranging anywhere from ambient to the boiling point of the solvent. An additive such as an acid source (such as toluenesulfonic acid, aqueous hydrochloric, etc.), a base (triethylamine, sodium hydroxide, etc.) or a physical catalyst (such as molecular sieves) may be added, in quantities ranging from catalytic to stoichiometric to excess. In practice, the cyclization of (XIII) often is very facile, particularly in the case where R is lower alkyl, and will occur spontaneously in the reaction medium of the alkylation of compound (XII). Cyclized compound (XIV) may be alkylated with the R4 group by first treatment with a base such as sodium hydride in a solvent such as dimethylformamide or dimethylsulfoxide, then an alkylating reagent (such as a halogen- or psuedohalogen-bearing compound) which provides the R4 group, to provide the compound of Formula (XV). At this point, compounds derived from bromoacetate alkylation of compound (XII) can be alkylated with appropriate R7 and R8 by treatment with a strong base such as sodium hydride, lithium diisopropylamide or sodium hexamethyldisilazide, and then alkylating agents bearing the R7 or R8 groups, thus resulting in the compound of Formula (XV).
Compound (XV) is a key intermediate which may be used to generate variations of Formula (I). For example, the carbonyl group of compound (XV) may be reduced with reagents such as lithium aluminum hydride, borane (complexed with tetrahydrofuran or other suitable ligands) or diisobutylaluminum hydride, which will generate a compound of Formula (XVI). The carbonyl group may be substituted with R5 and R6 groups using appropriately-substituted organolithium or organomagnesium reagents, to prepare compounds of Formula (XVII). The carbonyl group of compound (XV) may be converted to thiocarbonyl by treatment with reagents such as Lawesson""s Reagent or phosphorus pentasulfide in appropriate solvents (toluene, benzene, etc.). The thioamide group of compound (XVIII) may be converted to amidine using the method of Robba et al. (Tetrahedron Letters 1992, 33, 2803-2804), which involves treatment with an amine of formula R11xe2x80x94NH2 and a catalyst such as a mercury (II) salt. This will result in the synthesis of a compound of Formula (XIX).
Compounds of Formula (I) composed of a fused pyridine ring (Axe2x95x90CH) may be prepared using very similar technology to that presented in Scheme II. In this case, however, the starting material is not of the structure (XI), but rather 
of structural formula (XXV) (Scheme III). This compound may be prepared starting with a lactone compound of Formula (XX), which are available by dimerization of a ketoester R10C(xe2x95x90O)CH2CO2Et according to the method of Arndt (Org. Syn., Coll. Vol. III, p. 231), followed by deacylation according to the method of Collie et al. (J. Chem. Soc. 1907, 91, p. 787 and references therein). The ring oxygen atom may be replaced with nitrogen by treatment with conc. aq. ammonium hydroxide, according to the method of Wang (J. Heterocylic Chem. 1970, 1, 389-392). Compound (XXI) may be nitrated similarly to the transformation of compound (III) to give compound (XXII). The hydroxy groups of compound (XXII) may be converted to leaving groups Y using the techniques discussed above for the conversion of compound (IV) to (V). The C4 Y group may be selectively replaced with a nucleophilic X group, and the other Y group in compound (XXIV) may be replaced with NHR9 by treatment with a compound R9NH2, either with no solvent or an appropriate solvent (such as a high-boiling alcohol) at temperatures sufficiently elevated to effect coupling. Compound (XXV) 
may then be employed in the same general way as for compound (XI) to generate compounds of Formula (I).
Further functionalization of this class of compounds may be achieved using a compound of Formula (XXVI) (Scheme IV), which represents some pyridine or pyridine compound (either uncyclized, like compounds (XI) or (XXV), or a cyclized compound) bearing a leaving group Y. The Y group may be replaced with phenyl or pyridyl using coupling reactions employing a phenyl (or pyridyl) compound of Formula (XXVII) (or (XXIX)) and an appropriate palladium catalyst. For example, arylboronic acids (Zxe2x95x90B(OH)2) may be coupled to a heterocyclic halide using catalytic amounts of tetrakis(triphenylphosphine)palladium, which is the method of Suzuki, et al. (Synthetic Communications 1981, 11, p. 513-519). Other appropriate reagents for this coupling reaction includes organomagnesium (Zxe2x95x90MgBr or MgCl) reagents (with nickel (II) chloride catalysis according to the method of Sugimori et al., Synthetic Communications 1991, 21, p. 481-487) or organozinc (Zxe2x95x90ZnCl) reagents (according to the method of Negishi et al., J. Org. Chem. 1977, 42, p. 1821-1823).
Other carbon substituents may be introduced into compound (XXVI) by treatment with a sodium salt (generated by the use of a base such as sodium ethoxide or sodium hydride) of an active methylene or methine reagent (i.e. where B and D are groups which stabilize adjacent anions, such as keto, carboalkoxy, cyano, alkyl- or aryl-sulfonyl, etc.). The resulting compounds of Formula (XXXI) may be further modified by conversion of the B and D groups into R2 and R3 groups. Those skilled in the art of organic synthesis should readily understand possible variations of these conversions to prepare a number of different R1, R2 and R3 group substituents.
Preparation of compounds of Formula (I) wherein the R1 and R4 groups are taken together to form a ring may be accomplished beginning from a compound of Formula (XXXIII) (Scheme V), where Xxe2x80x2 is meant to designate a group NHR2, OH, SH or CHR2R3. This compound may be treated with a base (such as sodium hydride) in an appropriate solvent, followed by a reagent bearing reactive terminii on both ends (for example, a dihaloalkane, a haloester, etc.). The Xxe2x80x2 and amide NH groups will couple with such a reagent under these conditions to form the third ring of compound (XXXIV). The amide group may then be modified as described above to give then final product of Formula (XXXV).
Compounds of Formula (I) wherein the R4, R5 and R6 groups are taken together to form a heteroaromatic ring may 
be prepared using the strategy displayed in Scheme VI. Compound (XIV) may be converted to amidine (XXXVI), using the conditions described above for the preparation of compound (XIX). The amidine is treated with an xcex1-halo- or xcex1-hydroxyketone, under conditions such as refluxing alcohol, to afford the imidazole compound (XXXVII). Compound (XIV) may be converted to fused tetrazole compound (XXXVIII) using the conditions of Duncia et al. (J. Org. Chem. 1991, 56, p. 2395). 
The experimental methods listed below for Examples 1, 17, 24, 42, 131, 143, 155, and 248 may be used in the preparation of all the compounds shown in Tables I (pyrimidines) and II (pyridines).